Iron deficiency is an extremely common comorbidity in patients with heart failure, affecting up to 50% of all ambulatory patients. It is associated with reduced exercise capacity and physical well-being and reduced quality of life. Cutoff values have been identified for diagnosing iron deficiency in heart failure with reduced ejection fraction as serum ferritin, <100 μg/l, or ferritin, 100 to 300 μg/l, with transferrin saturation of <20%. Oral iron products have been shown to have little efficacy in heart failure, where the preference is intravenous iron products. Most clinical studies have been performed using ferric carboxymaltose with good efficacy in terms of improvements in 6-min walk test distance, peak oxygen consumption, quality of life, and improvements in New York Heart Association functional class. Data from meta-analyses also suggest beneficial effects for hospitalization rates for heart failure and reduction in cardiovascular mortality rates. A prospective trial to investigate effects on morbidity and mortality is currently ongoing. This paper highlights current knowledge of the pathophysiology of iron deficiency in heart failure, its prevalence and clinical impact, and its possible treatment options

1. STATE-OF-THE-ART REVIEW
Iron Deficiency in Heart Failure
An Overview
Stephan von Haehling, MD, PHD,a
Nicole Ebner, PHD,a
Ruben Evertz, MD,a
Piotr Ponikowski, MD, PHD,b
Stefan D. Anker, MD, PHDc,d
ABSTRACT
Iron deficiency is an extremely common comorbidity in patients with heart failure, affecting up to 50% of all ambulatory
patients. It is associated with reduced exercise capacity and physical well-being and reduced quality of life. Cutoff values
have been identified for diagnosing iron deficiency in heart failure with reduced ejection fraction as serum ferritin, <100
mg/l, or ferritin, 100 to 300 mg/l, with transferrin saturation of <20%. Oral iron products have been shown to have little
efficacy in heart failure, where the preference is intravenous iron products. Most clinical studies have been performed
using ferric carboxymaltose with good efficacy in terms of improvements in 6-min walk test distance, peak oxygen
consumption, quality of life, and improvements in New York Heart Association functional class. Data from meta-analyses
also suggest beneficial effects for hospitalization rates for heart failure and reduction in cardiovascular mortality rates. A
prospective trial to investigate effects on morbidity and mortality is currently ongoing. This paper highlights current
knowledge of the pathophysiology of iron deficiency in heart failure, its prevalence and clinical impact, and its possible
treatment options. (J Am Coll Cardiol HF 2019;7:36–46) © 2019 by the American College of Cardiology Foundation.
Iron is an essential element for all forms of human
life, mostly for its ability to accept and to donate
electrons, thereby switching between its ferrous
(bivalent, Fe2þ
) and its ferric (trivalent, Fe3þ
) form
(1). Iron deficiency (ID), on the other hand, affects up
to one-third of the world’s population (2). Populations
at high risk include infants, young children, adoles-
cents, elderly persons, and women, the last particu-
larly during menstrual periods and pregnancy. The
past decades have seen tremendous research effort
into ID in patients with chronic diseases with underly-
ing inflammatory activation, and these efforts have
finally yielded the understanding that patients with
heart failure (HF), chronic kidney disease, cancer,
and inflammatory bowel disease are likewise at
increased risk of developing ID. Thus, it is now under-
stood that childhood growth and blood loss as well as
inflammatory activity, even when only just detectable
as cytokine or C-reactive protein activation, are risk
factors for ID. This review paper traces the history of
ID and iron supplementation in HF and summarizes
the available data from clinical trials in order to guide
clinicians in their treatment decisions.
HISTORY OF TREATING IRON DEFICIENCY IN HF
Patients with HF are affected by severely reduced
exercise capacity and quality of life. On the lookout
for new ways of improving exercise capacity, re-
searchers from Tel Aviv started in the late 1990s to
ISSN 2213-1779/$36.00 https://doi.org/10.1016/j.jchf.2018.07.015
From the a
Department of Cardiology and Pneumology, University of Göttingen Medical Center, Göttingen, Germany; b
Department
of Heart Diseases, Wroclaw Medical University, Centre for Heart Diseases, Military Hospital, Wroclaw, Poland; c
Division of
Cardiology and Metabolism-Heart Failure, Cachexia and Sarcopenia, Department of Cardiology, Campus Virchow-Klinikum,
Charité-Universitätsmedizin Berlin, Berlin, Germany; and the d
Berlin-Brandenburg Center for Regenerative Therapies, Charité-
Universitätsmedizin Berlin, Berlin, Germany. Dr. von Haehling has consulted for Vifor Pharma, Roche, Bayer, Brahms; and has
received speaker fees from Boehringer Ingelheim, Novartis, Chugai Pharma, and Amgen. Dr. Anker has consulted for Vifor
Pharma, Boehringer Ingelheim, Bayer, Servier Pharmaceuticals, and Novartis; and has received grants through his institution from
Vifor Pharma, IIT, and Abbott Vascular. All other authors have reported that they have no relationships relevant to the contents of
this paper to disclose.
Manuscript received March 23, 2018; revised manuscript received June 29, 2018, accepted July 2, 2018.
J A C C : H E A R T F A I L U R E V O L . 7 , N O . 1 , 2 0 1 9
ª 2 0 1 9 B Y T H E A M E R I C A N C O L L E G E O F C A R D I O L O G Y F O U N D A T I O N
P U B L I S H E D B Y E L S E V I E R

2. treat anemic patients with HF with a combination of
subcutaneous erythropoietin and intravenous (IV)
iron sucrose (3). Mean hemoglobin concentration, left
ventricular ejection fraction (LVEF), and New York
Heart Association (NYHA) functional classes
improved significantly over 6 months of treatment
(3). These findings sparked an avalanche of research
into treatment of anemia in HF, culminating in a
program of large trials of the novel long-acting
erythropoietin derivative darbepoetin-alfa (Online
Refs. 1,2). The anemia treatment pathway was ulti-
mately left only after a large trial of darbepoetin-alfa
ended in disappointment. Indeed, the RED-HF
(Reduction of Events by Darbepoetin Alfa in Heart
Failure) study, a randomized, double-blind, placebo-
controlled trial in 2,278 patients with systolic HF and
mild to moderate anemia did not show any
improvement in the primary endpoint of death from
any cause or hospitalization for worsening HF; how-
ever, there was an increased rate of thromboembolic
events (13.5% vs. 10.0%, respectively; p ¼ 0.009) and
an increased risk of ischemic stroke (4.5% vs. 2.8%,
respectively; p ¼ 0.03) (4). In retrospect, it can be said
that the early study design, consisting of a combina-
tion therapy of erythropoietin and IV iron, hampered
the discovery that ID treatment may be worthwhile
even in the absence of anemia.
Shortly before the results of RED-HF were pub-
lished, a small open-label, nonrandomized, noncon-
trolled study in 16 patients with hemoglobin of #12 g/dl
and ferritin of #400 mg/l in NYHA functional class
II (56%) or III (44%) using IV iron administration
alone showed improvements in quality of life and
physical well-being over 3 months of follow-up (5).
At the end of the study, all patients were in NYHA
functional class II, their hemoglobin had risen, and
their quality-of-life score had improved. This point
is interesting, because the trials of darbepoetin-alfa
had all underutilized iron. Therefore, the confir-
mation of these early results in a double-blind,
randomized, placebo-controlled trial in 40 patients
with symptomatic HF was important (6). Another
small, randomized, observer-blinded study of IV
iron sucrose also showed that improvements in
exercise capacity measured by spiroergometry were
possible (Online Ref. 3).
DIAGNOSING IRON DEFICIENCY IN HF
The dilemma of correctly diagnosing ID arises from
the distinction between stored and circulating iron
and from the difference between mobilizable and
immobilizable iron. Because chronic HF, like chronic
kidney disease, inflammatory bowel disease, or
cancer, has been associated with increased
systemic inflammation, the patient’s status
plays an important role leading to functional
ID. Hepcidin, a peptide encoded by the HAMP
gene on chromosome 19 and secreted chiefly
by hepatocytes, is the main regulator of iron
uptake and release (1). Hepcidin controls
the activity of ferroportin, a transmembrane iron
exporter out of different cell types, that is, at the site
of iron absorption (gut mucosa cells in the duo-
denum), as well as at the site of iron storage (hepa-
tocytes, macrophages). Once ferroportin is bound by
hepcidin, it is destroyed in the lysosome, leading to
reduced iron release (7). Because bacteria are largely
dependent on the presence of iron for reproduction,
the peptide that inhibits its uptake and its mobiliza-
tion during periods of increased inflammatory
activity was originally named liver-expressed anti-
microbial protein (LEAP)-1. It was discovered in 2000
and later renamed hepatic bactericidal protein, or
hepcidin.
When research of ID started in cardiology, it was
unclear how to correctly arrive at its diagnosis. Reli-
able cutoff values were not available for HF but only
for kidney disease or cancer. Early studies of ID in HF,
therefore, used a ferritin concentration of #400 mg/l
or <100 mg/l or a combination of ferritin concentra-
tions ranging between 100 and 299 mg/l together with
a transferrin saturation (TSAT) level of <20% as
identifying criterion. After the latter cutoff values
were validated in a double-blind trial, they were
accepted and have been entered into the HF guide-
lines of the European Society of Cardiology (ESC) (8).
Consequently, current ESC HF guidelines give a Class
Ic recommendation to screen all HF patients for the
presence of ID by using serum ferritin and TSAT
measurement (8). Because these values are signifi-
cantly different from the cutoff values used in sub-
jects without chronic inflammation (usually ferritin
concentration of <20 mg/l), the point of alternative
diagnostic cutoffs is worth stressing. Treatment
should be considered regardless of the presence of
anemia. Table 1 highlights the most important cutoff
values for diagnosing ID across different clinical en-
tities in internal medicine.
PREVALENCE AND CLINICAL EFFECTS OF
IRON DEFICIENCY IN HF
ID is highly prevalent in patients with chronic and
acute HF; however, studies have used different defi-
nitions (13). A Canadian study in 12,065 patients with
newly diagnosed HF found 21% of all anemic patients
had absolute ID, as detected using discharge
A B B R E V I A T I O N S
A N D A C R O N Y M S
HF = heart failure
ID = iron deficiency
LVEF = left ventricular
ejection fraction
J A C C : H E A R T F A I L U R E V O L . 7 , N O . 1 , 2 0 1 9 von Haehling et al.
J A N U A R Y 2 0 1 9 : 3 6 – 4 6 Iron Deficiency in Heart Failure
37

3. international classification of disease codes, implying
complete or nearly complete depletion of iron stores
(Online Ref. 4). Nanas et al. (Online Ref. 5), on the
other hand, showed that a diagnosis based on serum
values of ferritin might be misleading. Those authors
used bone marrow biopsies from 37 anemic patients
with end-stage HF. They found that 27 patients (73%)
presented with ID in the bone marrow, even though
they had normal or nearly normal serum ferritin
levels. Several studies have applied the defining
criteria named above, that is, serum ferritin of
<100 mg/l or serum ferritin ranging from 100 to
299 mg/l in combination with a TSAT value of <20%.
Using data from 546 consecutive ambulatory patients
TABLE 1 Relevant Cut-Offs for the Diagnosis of ID in Different Fields of Internal Medicine
Clinical Trial
Completed Completed Completed Completed Completed Completed Completed
Study name
(Ref. #)
FERRIC-HF
(Online Ref. 3)
Toblli et al. (6) FAIR-HF (9) CONFIRM-HF (10) EFFECT-HF (11) IRON5 IRONOUT (12)
ClinicalTrial.gov
reference
NCT00125996 NCT00520780 NCT01453608 NCT01394562 NCT02998697 NCT02188784
Diagnosis HFrEF HFrEF HFrEF HFrEF HFrEF HF HFrEF
Number of patients 35 40 459 304 174 54 225
Randomization 2:1 (iron:placebo) 1:1 (iron:placebo) 2:1 (FCM:placebo) 1:1 (FCM:placebo) 1:1 (FCM:standard
of care)
1:1 (iron:placebo) 1:1 (FCM:placebo)
Blinding Double-blind Double-blind Double-blind Double-blind Open-label Double-blind Double-blind
Symptoms NYHA functional
class II–III
NYHA functional
class II–IV
NYHA functional
class II–III
NYHA functional
class II–III
NYHA functional
class II–III
NYHA functional
class II–III
NYHA functional
class II–IV
LVEF #45% #35% #40% in NYHA
functional class I,
#45% in NYHA
functional class III
#45% #45% <50% #40
Definition of iron
deficiency
Serum ferritin <100
ng/ml, or serum
ferritin 100–299
ng/ml with
TSAT <20%
TSAT <20%,
ferritin
<100 ng/ml
Serum ferritin <100
ng/ml, or serum
ferritin 100–299
ng/ml with
TSAT <20%
Serum ferritin <100
ng/ml, or serum
ferritin 100–299
ng/ml with
TSAT <20%
Serum ferritin <100
ng/ml, or serum
ferritin 100–
299 ng/ml with
TSAT <20%
Serum ferritin <100
ng/ml or 100–
300 ng/ml with
TSAT <20%
Serum ferritin <100
ng/ml, or serum
ferritin 100–299
ng/ml with
TSAT <20%
Hemoglobin <12.5 g/dl anemic
group, 12.5–
14.5 g/dl non
anemic group
<12.5 g/dl $9–#13.5 g/dl <15 g/dl #15 g/dl >8 and <13 g/dl
for men and <12
g/dl for women
$9.0–#13.5 g/dl
Natriuretic
peptides
Not included NT-proBNP Not included BNP >100 pg/ml,
NT-proBNP
>400 pg/ml
BNP >100 pg/ml,
NT-proBNP
>400 pg/ml
NT-proBNP
>4,000 pg/ml
NT-proBNP
Duration 16 weeks 25 weeks 24 weeks 52 weeks 24 weeks 90 days 16 week
Dosage Iron sucrose
200 mg weekly
until ferritin
>500 ng/ml
Iron sucrose 200
mg weekly for
5 weeks
200 mg ferric
carboxymaltose
200 mg ferric
carboxymaltose
500 mg ferric
carboxymaltose
3 times
Ferrous sulfate
200 mg 3 times
daily for 90
days
150 mg oral iron
polysaccharide
iron complex
(Feramax)
twice daily
Primary end point Change in absolute
pVO2 (ml/min)
from baseline
to week 18
Change in the
NT-proBNP
level and
inflammatory
status by CRP
Change in self-
reported PGA
score and NHYA
class from
baseline to
week 24
Change in 6-min walk
distance from
baseline to
week 24
Change in peak VO2
from baseline
to week 24
Change in 6MWT
from baseline
to 90 days
Change in peak
VO2 from
baseline to
week 16
BNP ¼ B-type natriuretic peptide; FCM ¼ ferric carboxymaltose; Hb ¼ hemoglobin; HF ¼ heart failure; HFpEF ¼ heart failure with preserved ejection fraction; HFrEF ¼ heart failure with reduced ejection
fraction; LVEF ¼ left ventricular ejection fraction; MR-proANP ¼ mid-reginal atrial natriuretic peptide prohormone; NT-proBNP ¼ N-terminal BNP prohormone; NYHA ¼ New York Heart Association; PGA ¼
patient global assessment; TSAT ¼ transferrin saturation.
von Haehling et al. J A C C : H E A R T F A I L U R E V O L . 7 , N O . 1 , 2 0 1 9
Iron Deficiency in Heart Failure J A N U A R Y 2 0 1 9 : 3 6 – 4 6
38

4. with HF, Jankowska et al. (14) found ID was present in
37%. Another study, in outpatients in German office-
based cardiology practices, using data from 1,198 pa-
tients with HF, found a prevalence of ID reaching
42.5% (15). Acknowledged risk factors for the devel-
opment of ID include female sex, a more advanced
stage of HF, higher levels of N-terminal-proB-type
natriuretic peptide (NT-proBNP), and higher serum
levels of C-reactive protein (14). In addition, the
presence of ID is an independent predictor of poor
exercise capacity (15) and worse survival (14,16).
IRON METABOLISM IN HUMANS
Iron itself is potentially toxic, because intracellular
reduction of molecular oxygen leads to the formation
TABLE 1 Continued
Clinical Trial
Recruiting Recruiting Recruiting Recruiting Recruiting Recruiting Recruiting
FAIR-HFpEF FAIR-HF 2 AFFIRM-AHF HEART-FID IRONMAN
NCT03074591 NCT03036462 NCT02937454 NCT03037931 NCT01978028 NCT02642562 NCT03218384
HFpEF HFrEF AHF after
restabilization
HFrEF HFrEF HFrEF HFrEF
200 1,200 1,100 3,014 20 1,300 32
1:1 (FCM:placebo) 1:1 (FCM:placebo) 1:1 (FCM:placebo) 1:1 (FCM:placebo) 1:1 (FCM:placebo) 1:1 (iron:placebo) 1:1 (FCM:placebo)
Double-blind Double-blind Double-blind Double-blind Double-blind Open label Double-blind
NYHA functional
class II-III
NYHA functional class
II-III
NYHA functional
class II-III
NYHA functional class
III-IV
NYHA functional
class II-III
NYHA functional
class II-IV
NYHA functional class
II-III
$45% together
with evidence of
diastolic
dysfunction
#45% <50% #35% #40% <45% <40% or $40% with
left atrial volume
index >28 ml/m2
)
and/or left
ventricular mass
index >95 g/m2
(women) or
>115 g/m2
(men)
Serum ferritin <100
ng/ml, or serum
ferritin 100–299
ng/ml with
TSAT <20%
Serum ferritin <100
ng/ml, or serum
ferritin 100–299
ng/ml with
TSAT <20%
Serum ferritin <100
ng/ml, or serum
ferritin 100–299
ng/ml with
TSAT <20%
Serum ferritin <100
ng/ml or 100–300
ng/ml with
TSAT <20%
Serum ferritin <100
ng/ml, or serum
ferritin 100–299
ng/ml with
TSAT <20%
TSAT <20% and/or
ferritin <100
mg/l
Serum ferritin <100
ng/ml, or serum
ferritin 100–299
ng/ml with
TSAT <20%
>9–#14 g/dl $9.5–#14 g/dl $8–#15 g/dl >9.0 and <13.5 g/dl
(women) or
<15.0 g/dl (men)
9.5-13.5 g/dl >9.0 and <13.5
g/dl (women)
or <15.0 g/dl
(men)
<13 g/dl for men
and <12 g/dl for
women
BNP >100 pg/ml,
NT-proBNP
>400 pg/ml,
MR-proANP
>125 pmol/l
Not included Not included NT-proBNP >600 pg/ml
or BNP >200 pg/ml
for patients with
normal sinus rhythm
or NT-proBNP
>1,000 pg/ml (or
BNP >400 pg/ml) for
patients with atrial
fibrillation
Not included NT-proBNP >250
ng/l in sinus
rhythm or
>1,000 ng/l in
atrial fibrillation
(or BNP of >75
pg/ml or 300
pg/ml,
respectively
Not included
52 weeks Event driven 52 weeks Event driven 12 weeks 120 weeks 4 weeks
500–2,000 mg ferric
carboxymaltose
according to Hb
and weight value
500–2,000 mg ferric
carboxymaltose
according to Hb and
weight value
500–1,500 mg ferric
carboxymaltose
according to Hb
and weight value
500–2,000 mg ferric
carboxymaltose
according to Hb and
weight value
500–2,000 mg ferric
carboxymaltose
according to Hb
and weight value
Iron (III)
isomaltoside
1,000
750 mg ferric
carboxymaltose
Change in 6-min
walk distance
from baseline to
week 24
Combined rate of
recurrent
hospitalizations for
HF and of
cardiovascular
death from baseline
to at least 12 months
of follow-up
HF hospitalizations
and
cardiovascular
death up to
52 weeks after
randomization
Incidence of death and
incidence of
hospitalization for
heart failure at least
12monthsoffollow-up
and change in 6MWT
distance after
6 months
Evaluate the effect of
ferric
carboxymaltose
on mitochondrial
gene activation
pattern after
12 weeks of
treatment
CV mortality or
hospitalization
for worsening
heart failure
Change in skeletal
muscle
mitochondrial
oxidative capacity
J A C C : H E A R T F A I L U R E V O L . 7 , N O . 1 , 2 0 1 9 von Haehling et al.
J A N U A R Y 2 0 1 9 : 3 6 – 4 6 Iron Deficiency in Heart Failure
39

5. of reactive oxygen species. Therefore, intracellular
and intravascular iron requires a “detoxifier,” intra-
cellularly in the form of ferritin and intravascularly
by binding to transferrin. Intravenously adminis-
tered iron preparations likewise require such a
“detoxifier” that usually has a composition similar to
the “envelope” function of ferritin (Figure 1). Side
effects of IV iron usually occur as a result of the
“envelope” composition rather than as a result of the
iron itself.
Oral iron tablets are prone to cause gastrointes-
tinal side effects, mostly as a result of direct iron
effects on the gut wall. Indeed, most oral iron
preparations contain ferrous iron (Fe2þ
) that is
directly absorbed through divalent metal transporter
(DMT)-1 into the gut mucosa cell. Nonheme (ferric)
iron present in vegetables and fruits is less well
absorbed and requires reduction by ferrireductase,
an enzyme likewise present in the gut mucosa,
before absorption. Ferrous iron (Fe2þ
), however,
cannot bind to transferrin and ferritin, and therefore
a reduction is necessary to enable such binding
(Figure 2) (17).
Inside the human body, iron not only plays a role
in oxygen transport but also in skeletal muscle, the
thyroid gland, the central nervous system, and in
immune function. In a single person, the overall
amount of iron is approximately 3 to 5 g, two-thirds
of which resides inside hemoglobin (18). Stored iron
bound to ferritin in several cell types has a much
smaller part: 800 to 1,000 mg in men and 300 to 500
mg in women, thus explaining the higher prevalence
of ID in female patients. With regard to function, the
body always prioritizes the use of iron for metabolic
purposes, with erythropoiesis having relative priority
over other functions (19). Because no means of iron
excretion exists, only the uptake in the duodenum
and the upper jejunum is regulated (20). Normal food
contains mostly nonheme (Fe3þ
) iron, approximately
5 to 6 mg per 1,000 kcal, a form that is less well
absorbed than heme iron (Fe2þ
) found in meat
(Online Ref. 6). Daily consumption is approximately
12 to 15 mg, but only 1 to 2 mg of this is ultimately
absorbed.
ESTIMATING THE IRON DEFICIT
Conventionally, the iron deficit seen in patients with
chronic disease had been estimated using Ganzoni’s
formula published in 1970 (21). This equation assumes
an ideal (target) hemoglobin value of 15.0 g/dl (body
weight of >35 kg) or 13.0 g/dl (lower body weight).
Because Ganzoni’s formula does not consider
replenishment of iron stores, an extra depot dose of
500 mg is usually added, as follows:
Iron deficit ðmgÞ ¼ ½body weight ðkgÞ
 ðtarget Hb À actual HbÞ
 2:4 þ depot ironŠ
The calculated result is 1,000 mg or higher in most
cases. Therefore, modern IV iron products provide
guidance for dosages listed in the drug information
sheet. Ferric carboxymaltose, for example, is usually
administered at a dose between 1,000 and 2,000 mg
to replenish iron stores; however, dosages should not
exceed 1,000 mg per week, which implies that a
heavy patient needs to return for a second dose in the
week after the first dose.
ORAL IRON THERAPY
Oral iron preparations usually contain Fe2þ
(Online
Ref. 7). Problems include the small amount of iron
absorbed in the gut, a metallic taste, and the fact that
up to 40% of patients experience side effects, most
frequently gastrointestinal discomfort such as nausea,
flatulence, abdominal pain, diarrhea, constipation,
and black staining of the stool (Online Ref. 8). Oral
iron preparations should be taken 30 to 60 mins before
to meals because iron absorption is highest in the
fasting state. The normal dosage is 100 to 200 mg per
day. Success is usually assumed when an increase in
reticulocytes or hemoglobin is observed after 1 or 3
weeks, respectively. Replenishing iron stores usually
takes 2 to 6 months (Online Ref. 9).
Two clinical studies evaluated the use of oral iron
preparations in patients with HF. The first study,
published in 2013, was named IRON 5-(Short Term
Oral Iron Supplementation in Systolic Heart Failure
Patients Suffering From Iron Deficiency Anemia) HF
and enrolled patients with an LVEF of <40% in
NYHA functional classes II to IV who had a hemo-
globin concentration between 9 and 12 g/dl, a
TSAT level of >20%, and a ferritin concentration of
<500 mg/l. Patients were randomized to 1 of 3 groups:
1) an oral ferrous sulfate therapy, 200 mg 3 times
daily, plus IV placebo; 2) an oral placebo plus IV iron
sucrose, 200 mg weekly; or 3) an oral and IV placebo.
Oral iron was administered over 8 weeks and IV iron
over 5 weeks. The calculated sample size was 39 per
group, making it the only clinical study in HF to
compare IV and oral iron supplementation. All treat-
ments were performed in a double-blinded fashion
(Online Ref. 10). Unfortunately, the trial was termi-
nated early after prolonged recruitment and funding
problems, with only 23 patients in the database.
von Haehling et al. J A C C : H E A R T F A I L U R E V O L . 7 , N O . 1 , 2 0 1 9
Iron Deficiency in Heart Failure J A N U A R Y 2 0 1 9 : 3 6 – 4 6
40

6. A significant increase in the patients’ peak oxygen
consumption was noted in the IV iron group after 3
months but not in the other groups (22). The mean
change in the patients’ TSAT level was 10 percentage
points with IV iron and 5 and 2 percentage points with
oral iron and placebo, respectively. Serum ferritin
increased from 167 Æ 149 mg/l to 293 Æ 270 mg/l in the
IV iron group and from 115 Æ 141 to 218 Æ 189 mg/l in
the oral iron group, but only the latter change was
statistically significant. These data, however, need to
be interpreted with caution, as most of the nonsig-
nificant results are probably explained by b-error.
The second trial to use oral iron therapy in HF was
the IRONOUT HF (Oral Iron Repletion Effects On Ox-
ygen Uptake in Heart Failure) trial, a phase II double-
blind, randomized, placebo-controlled trial of 225
patients with HF, an LVEF of <40%, and ID defined as
ferritin concentration of 15 to 100 mg/l or ferritin 101 to
299 mg/l with TSAT of <20% (12). Patients received
oral iron polysaccharide, 150 mg twice daily over 16
weeks. The primary endpoint of the trial, a change in
peak oxygen uptake from baseline to 16 weeks, was
not significantly different between the 2 groups at the
end of follow-up (iron: þ23 ml/min vs. placebo: À2
ml/min; p ¼ 0.5). Likewise, no significant change was
noted for the secondary endpoints, 6-min walk test
and NT-proBNP levels. A mild increase in serum
ferritin (þ11.3 mg/l; p ¼ 0.06) and TSAT (þ3.3%; p ¼
0.003) was noted with oral iron therapy (12). The
authors concluded that “these results do not support
use of oral iron supplementation in patients with HF
with reduced ejection fraction.”
INTRAVENOUS IRON THERAPY
Since the beginning of ID treatment in HF, oral iron
preparations were not the most promising treatment
approach due to pathophysiological considerations
such as the established overactivity of inflammatory
mediators in HF (23). Indeed, serum levels of tumor
necrosis factor (TNF) and interleukin (IL)-6 are known
to be elevated in patients with HF and are indepen-
dent predictors of poor survival (Online Ref. 11). In
addition, the gut wall itself has been shown to display
increased thickness in cases of HF (Online Ref. 12).
Therefore, early intervention trials were carried out
with IV iron treatment using 1 of the several different
formulations available on the market. Presently, the
usual route of administration is the IV route, and
treatment options are iron(III) gluconate, iron(III)
hydroxide sucrose, iron(III) hydroxide polymaltose
complex (ferric carboxymaltose), and ferumoxytol
(Online Ref. 13). A combination of the products in 1
sitting is generally not recommended. The latest
additions to the portfolio, that is, iron sucrose, ferric
carboxymaltose, and ferumoxytol, permit the appli-
cation of higher doses of iron in 1 sitting. Most studies
in patients with HF and ID have used either iron su-
crose (maximum dose in 1 sitting: 200 mg) or ferric
carboxymaltose (1,000 mg). Iron dextran does not
play a major role anymore in clinical routine (24).
The early small studies of IV iron in HF are sum-
marized in Table 2 and Figure 3. The first large-scale,
double-blind, placebo-controlled multicenter trial of
ferric carboxymaltose in patients with chronic HF was
published in 2009 (Online Ref. 14). This study, the
FAIR-HF (Ferinject Assessment in patients with IRon
deficiency and chronic Heart Failure) trial recruited
459 patients in NYHA functional class II (LVEF #40%)
or NYHA functional class III (LVEF #45%). With a
hemoglobin concentration ranging between 9.5 and
13.5 g/dl, the recruitment of anemic patients was not a
prerequisite. Patients had to have ID, defined as
serum ferritin of <100 mg/l or ferritin ranging from
100 to 300 mg/l, with TSAT of <20%. Patients were
randomly allocated in a 2:1 fashion to receive IV ferric
carboxymaltose or placebo and entered the trial in the
so-called correction phase, during which their calcu-
lated iron deficit (Ganzoni’s formula) was replenished
by weekly doses of 200 mg. A maintenance phase was
added during which patients received 200 mg of ferric
carboxymaltose per month. After 24 weeks of follow-
up, 50% of patients in the ferric carboxymaltose
group had improved according to the self-reported
patient global assessment (PGA), the primary end
point of the study, compared to 28% in the placebo
group (odds ratio [OR] for being in a better rank: 2.51;
FIGURE 1 Principal Structure of Ferritin and Intravenous Iron
J A C C : H E A R T F A I L U R E V O L . 7 , N O . 1 , 2 0 1 9 von Haehling et al.
J A N U A R Y 2 0 1 9 : 3 6 – 4 6 Iron Deficiency in Heart Failure
41

7. 95% confidence interval [CI]: 1.75 to 3.61; p < 0.001)
(27). The PGA describes the patient’s overall well-
being compared to the last assessment. Secondary
endpoints included NYHA functional class, 6-min
walk distance, and quality of life as assessed by the
Kansas City Cardiomyopathy Questionnaire and
showed, likewise, a statistically significant improve-
ment. These effects were seen regardless of whether
anemia was present at baseline. Publication of the
FAIR-HF study results yielded the first recommen-
dation to consider IV ferric carboxymaltose in the
2012 ESC HF guidelines (Online Ref. 15), which
followed the 2011 update of the National Heart
Foundation of Australia and Cardiac Society of
Australia and New Zealand guidelines for the
management of HF (grade B recommendation)
(Online Ref. 16).
The second large-scale trial of ferric carbox-
ymaltose in HF, the CONFIRM-HF (ferric Carbox-
ymaltOse evaluatioN on perFormance in patients
with IRon deficiency in coMbination with chronic
Heart Failure) trial, showed results very similar to
those of the FAIR-HF study. Likewise, CONFIRM-HF
was a double-blind, multicenter, prospective, ran-
domized controlled trial that enrolled ambulatory
patients with symptomatic HF in NYHA functional
class II or III with an LVEF of #45% and an elevated
level of either NT-proBNP or B-type natriuretic pep-
tide (BNP) (Online Ref. 17). Patients received between
500 and 2,000 mg of iron or placebo within the first 6
weeks in the study. Thereafter, patients received 500
mg of ferric carboxymaltose at each visit in weeks 12,
24, and 36 if ferritin and/or TSAT still indicated ID
(Online Ref. 17). Randomization was performed in 1:1
fashion, and treatment duration was 52 weeks. The
primary endpoint was the change in the 6-min
walking distance from baseline to 24 weeks. Addi-
tional assessments were done at 6, 36, and 52 weeks,
also including secondary endpoints such as PGA score
and safety. At 24 weeks, patients in the ferric car-
boxymaltose group had a significantly greater
FIGURE 2 Iron Uptake in the Duodenum and Release
Iron uptake in the duodenum and iron release from cells of the reticuloendothelial system by ferroportin, whose expression is tightly regulated by the expression of the
acute-phase reactant hepcidin. Adapted from von Haehling (17).
TABLE 2 Published and Ongoing Clinical Trials in HF With
Relevance for ID Treatment
Illness TSAT, % Ferritin, mg/l
No underlying illness <30
Chronic HF - <100
<20 100–299
Inflammatory bowel disease
Without increased activity <20 <30
With increased activity <20 <100
Chronic kidney disease
Treated with dialysis <25 <200
Without dialysis <25 <300
Cancer and chemotherapy-associated anemia
Without inflammatory activity <20 <100
With inflammatory activity <20 $100
Adapted from von Haehling et al. (9).
HF ¼ heart failure; ID ¼ iron deficiency; TSAT ¼ transferrin saturation.
von Haehling et al. J A C C : H E A R T F A I L U R E V O L . 7 , N O . 1 , 2 0 1 9
Iron Deficiency in Heart Failure J A N U A R Y 2 0 1 9 : 3 6 – 4 6
42

8. improvement in their 6-min walk distances than pa-
tients taking placebo (difference: 33 Æ 11 m; p ¼
0.002), and this effect was maintained to week 52
(28). A more recent clinical study named EFFECT-HF
(Effect of ferric carboxymaltose on exercise capacity
in patients with chronic heart failure and iron defi-
ciency) (29) showed that IV administration of ferric
carboxymaltose can also improve patients’ peak ox-
ygen consumption, as measured by spiroergometry
(2). A total of 174 patients were randomized, unfor-
tunately in a nonblinded fashion, to ferric carbox-
ymaltose therapy or standard of care (i.e., no
intervention) and were followed for 24 weeks. Most
patients were in NYHA functional class II at baseline.
Ferric carboxymaltose significantly increased serum
ferritin and transferrin saturation. At 24 weeks, peak
oxygen consumption had decreased in the control
group (least square means: À1.19 Æ 0.389 ml/min/kg)
but was maintained in the ferric carboxymaltose
group (À0.16 Æ 0.387 ml/min/kg; p ¼ 0.02). This result
was achieved by imputation of missing data by the
last-observation-carried-forward approach. In a
sensitivity analysis, in which missing data were not
imputed, peak oxygen consumption at 24 weeks
decreased by À0.63 Æ 0.375 ml/min/kg in the control
group and by À0.16 Æ 0.373 ml/min/kg in the IV iron
group; p ¼ 0.23.
Two meta-analyses were published between 2016
and 2017 with regard to IV iron treatment in HF. Jan-
kowska et al. (30) included 5 clinical studies yielding a
total number of 851 patients, 509 of whom received
iron sucrose or ferric carboxymaltose. IV iron therapy
was found to reduce the risk of the combined endpoint
of all-cause death or cardiovascular hospitalization
(OR: 0.44; 95% CI: 0.30 to 0.64; p < 0.0001) and the
combined endpoint of cardiovascular death or hospi-
talization for worsening HF (OR: 0.39; 95% CI: 0.24 to
0.63; p ¼ 0.0001). With regard to overall well-being
and quality of life, IV iron therapy resulted in a
reduction in NYHA functional class (p ¼ 0.001), an
increase in the 6-min walking test distance (þ31 m;
95% CI: 18 to 43; p < 0.0001), and an improvement
in quality of life, using different assessment tools (all
p # 0.01) (30). A second meta-analysis was published
in 2017, using data from 4 randomized controlled
trials including 839 patients, 504 of whom had
received ferric carboxymaltose (31). Patients taking
ferric carboxymaltose had lower rates of recurrent
cardiovascular hospitalizations and cardiovascular
mortality (OR: 0.59; 95% CI: 0.40 to 0.88; p ¼ 0.009).
Treatment with ferric carboxymaltose also reduced
recurrent HF hospitalizations and cardiovascular
mortality (OR: 0.53; 95% CI: 0.33 to 0.86; p ¼ 0.011)
and recurrent cardiovascular hospitalizations and
FIGURE 3 Major Publications in the Field of Iron Deficiency and Anemia in Heart Failure
J A C C : H E A R T F A I L U R E V O L . 7 , N O . 1 , 2 0 1 9 von Haehling et al.
J A N U A R Y 2 0 1 9 : 3 6 – 4 6 Iron Deficiency in Heart Failure
43

9. all-cause mortality (OR: 0.60; 95% CI: 0.41 to 0.88;
p ¼ 0.009) (31). These data suggest beneficial effects
of IV iron treatment in HF and led to designing the
prospective FAIR-HF 2 trial with a primary endpoint of
the combined rate of recurrent hospitalizations for HF
and of cardiovascular death. The trial is currently
ongoing and aims to recruit 1,200 patients.
TREATMENT OF IRON DEFICIENCY IN
HF GUIDELINES
Since 2012, the ESC guidelines have recommended
that all patients with HF should undergo testing for ID
by using serum assessment of ferritin and TSAT
(Online Ref. 17). Anemia should be ruled out by using
full blood count assessment, both are Class I, Level of
Evidence: C recommendations. This point has not
been changed in the 2016 version of the guidelines
(8), in which the treatment recommendation had
been updated after the publication of the CONFIRM-
HF trial to Class IIa, Level of Evidence: A. The state-
ment reads, “IV ferric carboxymaltose should be
considered in symptomatic patients (serum
ferritin <100 mg/l, or ferritin between 100 to 299 mg/l
and TSAT <20%) in order to alleviate HF symptoms
and improve exercise capacity and quality of life” (8).
The Central Illustration shows the diagnostic algo-
rithm for the treatment of iron deficiency in patients
with HF as recommended by current ESC guidelines
(32). The joint guidelines of the American Heart As-
sociation and American College of Cardiology pub-
lished in 2013 were less enthusiastic (33); however,
the 2017 update now states that “in patients with
NYHA functional class II and III HF and iron defi-
ciency (ferritin <100 mg/l or 100 to 300 mg/l if TSAT
is <20%), IV iron replacement might be reasonable to
improve functional status and quality of life giving
this recommendation a IIb level of evidence” (34).
The European guidelines currently advocate only the
use of ferric carboxymaltose, because large-scale tri-
als have been undertaken, and the drug’s safety has
been demonstrated in the HF population only with
this drug. The U.S. guidelines do not mention a spe-
cific type of iron but rather mention IV iron admin-
istration. Previous smaller trials have also used other
iron preparations, particularly iron sucrose, but large-
scale trials that could have been considered by the
guideline committees are still missing. Therefore, it
remains unclear if these are able to achieve similar
results.
CONCLUSIONS AND OUTLOOK
ID in HF with reduced ejection fraction has received
increasing attention over the last 18 years. The prev-
alence of ID reaches 50% among ambulatory patients
with HF, and ID is an independent predictor of
reduced exercise capacity, quality of life, and sur-
vival. Risk factors include female sex, more advanced
stage of HF, higher levels of NT-proBNP, and higher
serum levels of C-reactive protein. Relevant cutoff
values are ferritin of <100 mg/l or ferritin 100 to 300
mg/l when TSAT is <20%. It has been convincingly
shown that IV iron application leads to improvements
in quality of life, physical well-being, and exercise
capacity. Most studies, particularly those of relevant
size, have been conducted with ferric carboxymaltose
and have good overall safety profiles. Data from 2
meta-analyses suggest beneficial effects in terms of
reduced hospitalization rates for HF and cardiovas-
cular mortality. A large-scale prospective morbidity
and mortality trial is underway. The situation in HF
with preserved ejection fraction (HFpEF) is less clear,
and another prospective trial, the FAIR-HFpEF trial
commenced recruitment late in November 2017.
Likewise, uncertainty remains with regard to the
CENTRAL ILLUSTRATION Diagnostic Algorithm for
Treatment of Iron Deficiency in Patients With HF According to
ESC Guidelines and Expert Consensus Recommendations
* If significant anemia, initiate evaluation
** Re-evaluate iron status after 3-6 months
Symptomatic HFrEF
NYHA II-III
yes
no
no
yes
yes
Hemoglobin <15 g/dL*
Ferritin <100 µµg/L
or
Ferritin 100-299 µµg/L
with TSAT <20%
Consider IV iron
treatment**
No IV iron
treatment
von Haehling, S. et al. J Am Coll Cardiol HF. 2019;7(1):36–46.
Adapted with permission from Doehner et al. (32). *If anemia is significant, initiate an
evaluation. **Re-evaluate iron status after 3 to 6 months (Online Ref. 18). HFrEF ¼
heart failure with reduced ejection fraction; IV ¼ intravenous; NYHA ¼ New York Heart
Association.
von Haehling et al. J A C C : H E A R T F A I L U R E V O L . 7 , N O . 1 , 2 0 1 9
Iron Deficiency in Heart Failure J A N U A R Y 2 0 1 9 : 3 6 – 4 6
44

10. ideal timepoint of IV application after cardiac
decompensation. The AFFIRM-AHF (Study to
Compare Ferric Carboxymaltose With Placebo in Pa-
tients With Acute Heart Failure and Iron Deficiency)
trial, a randomized, double-blind placebo-controlled
trial comparing the effect of IV ferric carboxymaltose
in patients with ID who are hospitalized for acute HF,
is aimed at elucidating effects on hospitalization rates
and mortality in this population. Table 2 highlights
published and currently ongoing studies with rele-
vance to ID in HF.
For the time being, it appears sensible to test all
symptomatic patients with HF with reduced ejection
fraction for the presence of ID. A full blood count
needs to be performed as well. When ID is diag-
nosed, IV ferric carboxymaltose can be administered
as a bolus injection or as an infusion over 15 mins.
The label permits the use of ferric carboxymaltose
up to a hemoglobin concentration of 15 g/dl. A single
dosage cannot exceed 1,000 mg per week; dilutions
can be made in 0.9% sodium chloride. A typical
response is a sharp increase in the patient’s ferritin
level following the infusion, which can easily exceed
500 mg/l and will decline only very slowly over
several weeks to months. Reassessment of iron sta-
tus is useful after approximately 3 to 6 months.
However, whether this time frame is optimal has not
been prospectively tested, and it remains unclear if
1,000 mg or higher doses are optimal for all
patients.
ADDRESS FOR CORRESPONDENCE: Prof. Stephan
von Haehling, Department of Cardiology and Pneu-
mology, University of Göttingen Medical School,
Robert-Koch-Strasse 40, D-37075 Göttingen,
Germany. E-mail: stephan.von.haehling@web.de.
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KEY WORDS ferric carboxymaltose, heart
failure, iron deficiency, treatment
APPENDIX For supplemental references,
please see the online version of this paper.
von Haehling et al. J A C C : H E A R T F A I L U R E V O L . 7 , N O . 1 , 2 0 1 9
Iron Deficiency in Heart Failure J A N U A R Y 2 0 1 9 : 3 6 – 4 6
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